Classification of biological samples from individuals is not an exact science. In many instances, accurate diagnosis and safe and effective treatment of a disorder depends on being able to discern biological distinctions among morphologically similar samples, such as tumor samples. The classification of a sample from an individual into particular disease classes has typically been difficult and often incorrect or inconclusive. Using traditional methods, such as histochemical analyses, immunophenotyping and cytogenetic analyses, often only one or two characteristics of the sample are analyzed to determine the sample's classification, resulting in inconsistent and sometimes inaccurate results. Such results can lead to incorrect diagnoses and potentially ineffective or harmful treatment.
For example, acute leukemia was first successfully treated by Farber and colleagues in the 1940's, and it was recognized that treatment responses were variable (Farber, et al, NEJM 238:787–793 (1948)). Subtle differences in nuclear shape and granularity were suggestive of distinct subtypes of acute leukemia, but such morphological distinctions were difficult to reproduce (C. E. Forkner, Leukemia and Allied Disorders, (New York, Macmillan) (1938); E. Frei et al., Blood 18:431–54 (1961); Medical Research Council, Br Med J 1:7–14 (1963)). By the 1960s, these distinctions were further strengthened by enzyme-based histochemical analyses which demonstrated that some leukemias were periodic-acid-schiff (PAS) positive, whereas others were myeloperoxidase positive. This was the basis of the first attempts to classify the acute leukemias into those arising from lymphoid precursors (acute lymphoblastic leukemia, ALL) and those arising from myeloid precursors (acute myeloid leukemia, AML). This classification was further solidified by the development in the 1970s of antibodies recognizing either lymphoid or myeloid cell surface molecules. Most recently, particular subtypes of acute leukemia have been found to be associated with specific chromosomal translocations; for example, the t(12;21)(p13;q22) translocation occurs in 25% of patients with ALL, whereas the t(8;21)(q22;q22) occurs in 15% of patients with AML.
No single test is currently sufficient to establish the diagnosis of AML vs. ALL. Rather, current clinical practice involves an experienced hematopathologist's interpretation of the tumor's morphology, histochemistry, immunophenotyping and cytogenetic analysis, each of which is performed in a separate, highly specialized laboratory. Correct distinction of ALL from AML is critical for successful treatment: chemotherapy regimens for ALL generally contain corticosteroids, vincristine, methotrexate, and L-asparaginase, whereas most AML regimens rely on a backbone of daunorubicin and cytarabine. While remissions can be achieved using ALL therapy for AML (and vice versa), cure rates are markedly diminished, and unwarranted toxicities are encountered. Thus, the ability to accurately classify a biological sample as an AML sample or an ALL sample is quite important.
Furthermore, important biological distinctions are likely to exist which have yet to be identified due to the lack of systematic and unbiased approaches for identifying or recognizing such classes. Thus, a need exists for an accurate and efficient method for identifying biological classes and classifying samples.